The goals of this proposed study is to employ insulin receptor (IR) and insulin-like growth factor I receptor (IGFR) CDNA-containing retroviruses to elucidate the biochemical basis of cell transformation. IR and IGFR are two members of the receptor PTK family which play an important regulatory role in cellular metabolic activities and mitosis. We have demonstrated that the transforming and tumorigenic potential of IR and IGFR can be manifested by placing part of their CDNA sequences in retroviruses. Our specific aims in this study are 1) identification of the structural basis responsible for activation of the transforming and tumorigenic potential of human IR and IGFR; 2) establishment of mammalian cell lines transformed by IR and IGFR-containing retroviruses mutant IR and IGFR proteins and correlation with their differential transforming potential; and 4) identification of potential cellular substrates important for cell transformation by mutant IR and IGFR proteins. It is hoped that this study will further our understanding of the mechanism of cell transformation by those receptor PTK genes.